Pharmaceutical combinations

ABSTRACT

Pharmaceutical combinations suitable for treating the lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men are described herein. The combinations contain an alpha-adrenoceptor antagonist and a muscarinic antagonist that may be administered simultaneously, separately or sequentially. The methods of treatment using the combinations are particularly suitable for treating moderate or severe LUTS.

[0001] This application claims the benefit of U.S. Provisional PatentApplication No. 60/181,310 filed Feb. 9, 2000, incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to pharmaceutical combinations suitablefor treating the lower urinary tract symptoms (LUTS) associated withbenign prostatic hyperplasia (BPH) in men, which combinations contain analpha-adrenoceptor antagonist and a muscarinic antagonist. Thecombinations of the invention are particularly suitable for treatingmoderate or severe LUTS.

BACKGROUND

[0003] BPH is a progressive, nearly universal condition in aging mencharacterized by a nodular enlargement of prostatic tissue resulting,through obstruction of the urethra, in variable degrees of bladderoutlet obstruction. The disorder is not a major cause of death, but itis a leading cause of morbidity in elderly men and is associated with avariety of lower urinary tract symptoms. LUTS in males include, interalia, increased frequency of urination, nocturia, a poor urine streamand hesitancy or delay in starting the urine flow. Chronic consequencesof BPH can include hypertrophy of bladder smooth muscle, a decompensatedbladder and an increased incidence of urinary tract infection. Thespecific biochemical, histological and pharmacological properties of theprostate adenoma leading to the bladder outlet obstruction are not yetknown. However, the development of BPH is considered to be aninescapable phenomenon for the aging male population. BPH is commonlyseen in men over the age of 50 and is observed in approximately 70% ofmales over the age of 70. Currently, in the United States, the method ofchoice for treating BPH is the administration of alpha₁-adrenoceptorantagonists and, to a lesser extent, surgery, usually involvingtransurethral resection of the prostate (TURP). The limitations ofsurgery for treating BPH include the morbidity associated with anoperative procedure in elderly men, persistence or recurrence ofobstructive and irritative symptoms, as well as the significant cost ofsurgery. In general, alpha₁-adrenoceptor antagonists are used only inthe treatment of patients with mild or moderate LUTS.

[0004] LUTS are recognized as arising from changes in urethralresistance induced by the enlarging prostate; the outflow of urine isrestricted and secondary changes are induced in the bladder. Acharacteristic pattern of unstable bladder contractions, also known asirritable bladder, is often observed in men with morphological BPH.

[0005] Although LUTS can arise from many causes, abnormally highactivity in the sympathetic nervous system is considered a primedeterminant. Noradrenaline, a neurotransmitter released from sympatheticnerve terminals, contracts the prostatic smooth muscle that surroundsthe urethra, increases urethral resistance and thereby reduces uroflow.

[0006] Alpha-adrenergic receptors (herein also referred to as“alpha-adrenoceptors” or as “alpha-receptors”) are specific proteinrecognition sites loaded in the peripheral and central nervous systemsand other tissues throughout the body. Neurotransmitters, such asnoradrenaline, control many physiological processes via an action onthese receptors and thereby transmit information between cells orinfluence cells or influence biochemical processes within the cell. Manyagents capable of modifying noradrenaline activity onalpha-adrenoceptors have been developed over the last 40 years. Drugsactive at alpha-adrenoceptors can be broken down into two major classes,agonists and antagonists. Agonists, of which phenylephrine andmethoxamine are examples, activate the receptor system in the same wayas the endogenous neurotransmitters, adrenaline and noradrenaline.Antagonists, of which phenoxybenzamine and prazosin are examples, do notactivate the receptor, but block the actions of the endogenousneurotransmitters.

[0007] Different alpha-adrenoceptor types have been discovered over theyears including alpha₁-adrenoceptors and alpha₂-adrenoceptors. Thesereceptor types are now considered to be subdivided further into subtypesincluding alpha_(1A, 1B, 1D, 1H, 1L) and _(1N).

[0008] Alpha₁-adrenoceptors are known to mediate the contraction ofvascular (arterial and venous) and prostatic smooth muscle.Alpha₁-adrenoceptor antagonists have been widely used as first linetherapy for the treatment of hypertension and, more recently, for thesymptomatic relief of BPH (see Kenny et al, Expert Opin in Invest Drugs,1995, 4, 915-923).

[0009] Alpha-adrenoceptor antagonists are known to relieve theobstruction by causing relaxation of the prostate smooth muscle, adecrease in urethral resistance and increased uroflow. As a result ofthese changes, male patients with the clinical symptoms of mild-moderateBPH experience a moderate improvement in symptoms. The magnitude of theeffect is considerably less than that achieved after surgery.

[0010] LUTS, although traditionally associated with BPH, can be found inboth men and women. It is noted that women, although they of course donot develop morphological BPH, also suffer due to unstable bladdercontractions. The clinical symptoms, particularly frequency and urgency,are similar in women and men.

[0011] Bladder excitability is under control of the parasympatheticnervous system that releases the neurotransmitter acetylcholine.Acetylcholine acts on protein recognition sites in the bladder calledantimuscarinic receptors, producing an increase in electricalexcitability of the bladder and concentration of bladder muscle.Unstable bladder is known to arise due to abnormal excitability orcontractility.

[0012] Drugs active at muscarinic receptors can be broken into two majorclasses, agonists and antagonists. Agonists activate the receptor systemin the same way as the endogenous neurotransmitter acetylcholine.Muscarinic antagonists (herein referred to as “antimuscarinics”, ofwhich atropine and hyoscine are examples) do not activate the receptor,but block the actions of the endogenous transmitter. Differentmuscarinic receptor types have been discovered over the years includingM₁, M₂ and M₃.

[0013] Antimuscarinic agents are known to relieve many of the symptomsarising from unstable or irritable bladder in women experiencing urinaryurge incontinence. The combination of Hyoscyamine and Doxazosin has alsobeen found to be efficacious in treating these symptoms in women (see,e.g., Serels, S., et al., Neurourology and Urodynamics, 17, 31-36(1998)). However, in normal circumstances, the LUTS arising fromBPH-induced unstable bladder contractions in men, should not be treatedwith antimuscarinics. Indeed the use of antimuscarinics in the treatmentof LUTS in men with BPH is contraindicated as urinary retention,requiring catheterization or surgery, may result (see, M. Caine, et al.,Br. J. Urol., 47(2), 193-202 (1975))

SUMMARY

[0014] The present invention provides a combination of analpha-adrenoceptor antagonist and a muscarinic antagonist for use as amedicament. In particular, it teaches the use of an alpha-adrenoceptorantagonist in combination with a muscarinic antagonist in themanufacture of a medicament for treating the lower urinary tractsymptoms associated with benign hyperplasia in mammals. In oneembodiment, the medicament (or product) includes a firstpharmaceutically acceptable composition containing an alpha-adrenoceptorantagonist and a second pharmaceutically acceptable compositioncontaining a muscarinic antagonist wherein the product is a combinedpreparation for simultaneous, separate or sequential use of the firstcomposition and the second composition.

[0015] In another embodiment of the present invention, a pharmaceuticalcomposition is provided which comprises an alpha-adrenoceptorantagonist, a muscarinic antagonist and a pharmaceutically acceptablecarrier. The composition may be used in the treatment of lower urinarytract symptoms associated with benign hyperplasia in mammals.

[0016] In yet another embodiment of the present invention, a method oftreating the lower urinary tract symptoms associated with benignprostatic hyperplasia is provided which includes administering to asubject (or mammal) in need thereof an effective amount of analpha-adrenoceptor antagonist in combination with a muscarinicantagonist. The combination may be administered separately,simultaneously or sequentially.

DETAILED DESCRIPTION

[0017] Reference to an alpha-adrenoceptor antagonist and/or to amuscarinic antagonist, both in this disclosure and the appendant claims,shall at all times be understood to include all active forms of suchagents, including the free form thereof (e.g. the free and/or base form)and also all pharmaceutically acceptable salts, polymorphs, hydrates,silicates, stereo-isomers, (e.g. diastereisomers and enantiomers) and soforth. Active metabolites of either the alpha-adrenoceptor antagonist orthe muscarinic antagonist, in any form, are also included.

[0018] The alpha-adrenoceptor antagonist can be selective foralpha₁-adrenoceptors or it can be non-selective, exhibiting antagonistactivity at both the alpha₁ and alpha₂ receptors. Antagonists selectivefor the alpha₁-adrenoceptor are preferred. In the context of the knownalpha₁-adrenoceptor subtypes, antagonists at _(1A, 1B, 1D, 1H, 1N) and_(1L) are equally preferred.

[0019] Suitable alpha₁-adrenoceptor antagonists include4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline(as described in example 19 of WO 98/30560), alfuzosin, indoramin,maftopidil, tamsulosin, doxazosin, terazosin, abanoquil, prazosin andpharmaceutically acceptable salts thereof. Preferred alpha₁-adrenoceptorantagonists include4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline,doxazosin, terazosin, indoramin, abanoquil, and prazosin, and thepharmaceutically acceptable salts thereof (especially doxazosinmesylate, terazosin hydrochloride, abanoquil mesylate and prazosinhydrochloride)

[0020] Further alpha-adrenoceptor antagonists which are reported to beselective for the alpha₁ receptor include: Recordati 15/2739, SNAP 1069,SNAP 5089, RS 17053 and SL 89.0591 (Kenny, et al., Expert Opin in InvestDrugs, 4, 915-923 (1995)).

[0021] Suitable non-selective alpha-adrenoceptor antagonists includephentolamine, trazodone, dapiprazole and phenoxybenzamine.

[0022] The alpha-adrenoceptor antagonists useful in this invention maybe widely chosen from among those already known to the art orsubsequently discovered and/or hereafter discovered and/or hereafterdeveloped. In addition to those specifically identified above,alpha-antagonists and salts thereof have been widely disclosed in thepatent literature, including U.S. Pat. Nos. 5,599,810; 5,340,814;5,508,279; 4,755,507; 4,188,390; 4,026,894; 3,511,836; 4,315,007;3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and2,599,000, each of which is incorporated herein by reference.

[0023] The alpha-adrenoceptor antagonism of a compound, and thereforeits suitability for use in the present invention, can be determinedusing a number of conventional assays in vitro. Suitable assays includethose disclosed in U.S. Pat. No. 5,599,810 which uses rabbit aorta todetermine alpha₁-adrenoceptor antagonist activity and U.S. Pat. No.5,340,814 which employ rat brain cortex to determine antagonistactivity. Both of these patents are incorporated herein by reference.

[0024] The muscarinic antagonist can be selective for M₃ receptors or itcan be non-selective, exhibiting antagonism at M₁, M₂ and M₃.Antagonists selective for the M₃ receptor are preferred.

[0025] Suitable M₃ receptor selective muscarinic antagonists aredarifenacin and pharmaceutically acceptable salts thereof.

[0026] Suitable non-selective muscarinic antagonists include atropine,fluvoxate, hyoscine, oxybutynin, tolterodine, propantheline,propiverine, trospium and the pharmaceutically acceptable salts thereof.

[0027] Of the foregoing, darifenacin, tolterodine and oxybutynin andpharmaceutically acceptable salts thereof are especially preferred,particularly darifenacin citrate.

[0028] The muscarinic antagonists useful in this invention may be widelychosen from among those already known to the art or subsequentlydiscovered and/or hereafter discovered and/or hereafter developed. Inaddition to those specifically identified above, pyrrolidineantimuscarinic antagonists have been disclosed in the patent literature,including U.S. Pat. Nos. 5,233,053 and 5,096,890, both of which areincorporated herein by reference.

[0029] The muscarinic antagonist activity of a compound, and thereforeits suitability for use in the present invention, can be determinedusing a number of conventional assays in vitro (see, Wallis and Napier,Life Sci, 64, 395-401, (1997)).

[0030] A suitable combination is a muscarinic antagonist and anon-selective alpha-adrenoceptor antagonist.

[0031] Preferred combinations are a muscarinic antagonist with aselective alpha₁-adrenoceptor antagonist and a non-selectivealpha-antagonist with a muscarinic antagonist that is selective for theM₃ receptor.

[0032] A more preferred combination is a selective alpha₁-adrenoceptorantagonist and a muscarinic antagonist that is selective for the M₃receptor subtype. The most preferred is the combination of anyalpha-adrenoceptor antagonist with darifenacin.

[0033] Preferred specific combinations include doxazosin withdarifenacin;4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolineand darifenacin; and pharmaceutically acceptable salts thereof.

[0034] Administering both therapeutic agents produces an effect that isgreater than that of the alpha-adrenoceptor antagonist administeredalone. This is advantageous in that it allows for a smaller amount ofthe alpha-adrenoceptor antagonist to be administered to provide atherapeutic effect. A further advantage is that therapy can be effectedfor patients who, for example, do not respond adequately to the use ofthe alpha-adrenoceptor antagonist at what would be considered a maximalstrength dose.

[0035] According to one aspect of the present invention, there isprovided a product (medicament) comprising a first pharmaceuticallyacceptable composition containing an alpha-adrenoceptor antagonist and asecond pharmaceutically acceptable composition containing a muscarinicantagonist for use as a combined preparation for simultaneous, separateor sequential use in treating the lower urinary tract symptomsassociated with benign hyperplasia in mammals.

[0036] In one embodiment, the alpha-adrenoceptor antagonist in the firstcomposition is non-selective. Preferably the alpha-adrenoceptorantagonist in the first composition is selective for α₁ receptors. Morepreferably the alpha₁-adrenoceptor antagonist in the first compositionis selected from4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinalzoline,doxazosin, tetrazosin, abanoquil, prazosin and indoramin andpharmaceutically acceptable salts thereof.

[0037] The muscarinic antagonist in the second composition may benon-selective. Preferably the muscarinic antagonist in the secondcomposition is selected from darifenacin, tolterodine and oxybutynin andpharmaceutically acceptable salts thereof. More preferably themuscarinic antagonist in the second composition is selective for M₃receptors. Most preferably the muscarinic antagonist in the secondcomposition is darifenacin and pharmaceutically acceptable saltsthereof.

[0038] The present invention provides for the administering of each ofthe antagonists separately but as part of the same therapeutic treatmentprogram or regimen, and it is contemplated that separate administrationof each compound, at different times and by different routes, willsometimes be recommended. Thus the two components need not necessarilybe administered at essentially the same time. In the preferredembodiment the alpha-adrenoceptor antagonist will be given several daysprior to initiation of the muscarinic antagonist either daily or “ondemand”. In another preferred embodiment, administration is timed sothat the peak pharmacokinetic effect of the alpha₁-adrenoceptorantagonist precedes the peak pharmacokinetic effect of the muscarinicantagonist. If co-administered separately, it is also preferred thatboth components be administered in an oral dosage form.

[0039] The product may comprise a kit. The kit may comprise a containerfor containing the separate compositions such as a divided bottle or adivided foil packet, wherein each compartment contains a plurality ofdosage forms (e.g., tablets) comprising either the alpha₁-adrenoceptorantagonist or the muscarinic antagonist.

[0040] Alternatively, rather than separating the activeingredient-containing dosage forms, the kit may contain separatecompartments each of which contains a whole dosage which comprisesseparate compositions. An example of this type of kit is a blister packwherein each individual blister contains two tablets, one tabletcomprising the alpha-adrenoceptor antagonist, the other comprising themuscarinic antagonist.

[0041] Typically the kit comprises directions for the administration ofthe separate components. Such instructions would cover situations suchas:

[0042] i) the dosage form in which the components are administered (e.g.oral and parenteral),

[0043] ii) when the component parts of the product are administered atdifferent dosage intervals, or

[0044] iii) when titration of the individual components of thecombination is desired by the prescribing physician. The container mayhave deposited thereon a label that describes the contents therein andany appropriate warnings.

[0045] An example of such a kit is a so-called blister pack. Blisterpacks are well known in the packaging industry and are widely used forthe packaging of pharmaceutical unit dosage forms such as tablets,capsules, and the like. Blister packs generally consist of a sheet ofrelatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process recesses areformed in the plastic foil. The recesses have the size and shape of thetablets or capsules to be packed. Next, the tablets or capsules areplaced in the recesses and the sheet of relatively stiff material issealed against the plastic foil at the face of the foil which isopposite from the direction in which the recesses between the plasticfoil and the sheet. Preferably, the strength of the sheet is such thatthe tablets or capsules can be removed from the blister pack by manuallyapplying pressure on the recesses whereby an opening is formed in thesheet at the place of the recess. Tablet(s) or capsule(s) can then beremoved by means of the opening.

[0046] It may be desirable to provide a memory aid on the kit, e.g., inthe form of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen during which the tablets orcapsules so specified should be ingested. Another example of such amemory aid is a calendar printed on the card, e.g. as follows “FirstWeek, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, .. . ”, etc. Other variations of memory aids will be readily apparent. A“daily dose” can be a single tablet or capsule or several pills orcapsules to be taken on a given day. Also a daily dose of the firstcompound can consist of one tablet or capsule while a daily dose of thesecond compound can consist of several tablets or capsules and viceversa. The memory aid should reflect this.

[0047] It is also within the scope of the present invention that boththe alpha-adrenoceptor antagonist and the muscarinic antagonist may bepresent in a single composition. Thus according to a further aspect ofthe invention, there is provided a pharmaceutical composition containingan alpha-adrenoceptor antagonist, a muscarinic antagonist and apharmaceutically acceptable carrier.

[0048] Suitable alpha-adrenoceptor antagonists include those that arenon-selective. Preferably the alpha-adrenoceptor antagonist is selectivefor the α₁ receptor. More preferably the alpha-adrenoceptor antagonistis selected from4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline,doxazosin, tetrazosin, abanoquil, prazosin and indoramin andpharmaceutically acceptable salts thereof.

[0049] Suitable muscarinic antagonists include those that arenon-selective. Preferably the muscarinic antagonist is selected fromdarifenacin, tolterodine and oxybutynin and pharmaceutically acceptablesalts thereof. More preferably the muscarinic antagonist is selectivefor M₃ receptors. Most preferably the muscarinic antagonist in thesecond composition is darifenacin and pharmaceutically acceptable saltsthereof.

[0050] Most preferred is a composition containing a combination of anyalpha-adrenoceptor antagonist with darifenacin. Preferred specificcombinations include: doxazosin and darifenacin; and4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolineand darifenacin; and pharmaceutically acceptable salts thereof.

[0051] The compositions of the present invention, both those thatcontain only one component and those that contain both, may be suitablefor topical, oral, parenteral or rectal administration. The compositionsmay be formulated to provide immediate or sustained release of thetherapeutic agent. Particularly suitable delayed or sustained releaseformulations are those disclosed in WO 97/09980.

[0052] The compounds of the invention can be administered alone but willgenerally be administered as an admixture with a suitable pharmaceuticalexcipient, diluent or carrier selected with regard to the intended routeof administration and standard pharmaceutical practice.

[0053] For example, the compounds of the invention can be administeredorally, buccally or sublingually in the form of tablets, capsules,ovules, elixirs, solutions or suspensions, which may contain flavoringor coloring agents, for immediate-, delayed-, modified-, sustained-,pulsed- or controlled-release applications.

[0054] Generally, tablets contain various excipients such asmicrocrystalline cellulose, lactose, sodium citrate, calcium carbonate,dibasic calcium phosphate and glycine, disintegrants such as starch(preferably corn, potato or tapioca starch), sodium starch glycollate,croscarmellose sodium and certain complex silicates, and granulationbinders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.Additionally, lubricating agents such as magnesium stearate, stearicacid, glyceryl behenate and talc may be included. Tablets may bemanufactured by any standard tablet-making process, for example, directcompression or a wet or dry granulation process. The tablet cores mayalso be coated with one or more appropriate overcoats.

[0055] Solid compositions of a similar type are also employed as fillersin gelatin capsules. Preferred excipients in this regard includelactose, milk sugar, cellulose, starch or high molecular weightpolyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of this invention can be combined with various sweeteningagents, flavoring agents, coloring agents or dyes, emulsifying agentsand/or suspending agents, diluents (e.g., water, ethanol, propyleneglycol, glycerin and mixtures thereof) and combinations thereof.

[0056] The compounds of the invention can also be administeredparenterally, for example, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrally,intrasternally, intracranially, intramuscularly or subcutaneously, orthey may be administered by infusion techniques. For such parenteraladministration they are best used in the form of a sterile aqueoussolution which may contain other substances, for example, enough saltsor glucose to make the solution isotonic with blood. If necessary, theaqueous solutions should be suitably buffered (preferably to a pH from 3to 9). The preparation of suitable parenteral formulations under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell-known to those skilled in the art.

[0057] For application topically to the skin, the compounds of theinvention can be formulated as a suitable ointment containing the activecompound suspended or dissolved in, for example, a mixture with one ormore of the following: mineral oil, liquid petrolatum, white petrolatum,propylene glycol, polyoxyethylene or polyoxypropylene compound,emulsifying wax and water. Alternatively, they can be formulated as asuitable lotion or cream, suspended or dissolved in, for example, amixture of one or more of the following: mineral oil, sorbitanmonostearate, a polyethylene glycol, liquid paraffin, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-oxtyldodecanol, benzyl alcohol andwater.

[0058] The alpha-adrenoceptor antagonist and/or the muscarinicantagonist may also be used in combination with a cyclodextrin.Cyclodextrins are known to form inclusion and non-inclusion complexeswith drug molecules. Formation of a drug-cyclodextrin complex may modifythe solubility, dissolution rate, bioavailability and/or stabilityproperty of a drug molecule. Drug-cyclodextrin complexes are generallyuseful for most dosage forms and administration routes. As analternative to direct complexation with the drug the cyclodextrin may beused as an auxiliary additive, e.g., as a carrier, diluent orsolubilizer. Alpha-, beta- and gamma-cyclodextrins are most commonlyused and suitable examples are described in WO 91/11172, WO 94/02518 andWO 98/55148.

[0059] Other pharmaceutical components may also be optionally includedas part of the combinations useful in this invention so long as they donot interfere or adversely affect the effects of the alpha-adrenoceptorantagonist/muscarinic antagonist combination.

[0060] The exact dose of each component administered will, of course,differ depending on the specific components prescribed, on the subjectbeing treated, on the severity of the LUTS, on the manner ofadministration and on the judgement of the prescribing physician. Thus,because of patient-to-patient variability, the dosages given below are aguideline and the physician may adjust doses of the compounds to achievethe treatment that the physician considers appropriate for the patient,male or female. In considering the degree of treatment desired, thephysician must balance a variety of factors such as the age of thepatient and the presence of other diseases or conditions (e.g.cardiovascular disease). In general, the muscarinic antagonist will beadministered in a range of from 0.5 to 200 mg per day, preferably 10 to125 mg per day, more preferably 25 mg to 100 mg per day. Thealpha-adrenoceptor antagonist will generally be administered in anamount of from 0.01 mg to 50 mg per day, preferably from 0.5 to 10 mgper day.

[0061] Doxazosin, when in combination, will be administered in the range0.25 mg to 16 mg per day, preferably 2 mg to 4 mg per day. Tolterodinewill be administered twice a day in the range 0.2 mg to 2 mg per day,preferably from 0.5 mg to 1 mg per day and darifenacin will beadministered in the range 0.5 mg to 5 mg twice a day, preferably 1 mg or2 mg. All weights quoted above refer to the weight of the compounds asthe free base.

[0062] Methods of preparing various pharmaceutical compositions with acertain amount of active ingredient are known, or will be apparent inlight of this disclosure, to those skilled in this art. For examples ofmethods of preparing pharmaceutical compositions, see, Remington'sPharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15^(th)Edition (1975).

[0063] The invention is further illustrated by the following,non-limiting examples.

EXAMPLES Example 1

[0064] Immediate release doxazosin tablet: Ingredient % w/w DoxazosinMesylate 4.05 Microcrystalline Cellulose 125.28 Lactose 66.67 SodiumStarch Glycollate 2.00 Magnesium stearate 2.00 Total weight 200.00

[0065] The doxazosin mesylate, microcrystalline cellulose, lactose andsodium starch glycollate were blended together, passed through a screen,then blended again. The blend was lubricated with magnesium stearate andcompressed using a tablet press. The resulting tablet was then given afilm coating.

Example 2

[0066] Immediate release darifenacin tablet: Ingredient % w/wDarifenacin hydrobromide 2.976 Microcrystalline Cellulose 131.024Calcium phosphate dibasic 60.000 Croscarmellose sodium 4.000 Magnesiumstearate 2.000 Total weight 200.000

[0067] The darifenacin hydrobromide, microcrystalline cellulose, lactoseand sodium starch glycollate were blended together, passed through ascreen, then blended again. The blend was lubricated with magnesiumstearate and compressed using a tablet press. The resulting tablet wasthen given a film coating.

Example 3

[0068] Combination immediate release darifenacin/doxazosin tablet:Ingredient % w/w Doxazosin Mesylate 4.05 Darifenacin hydrobromide 2.976Microcrystalline Cellulose 125.28 Lactose 63.694 Sodium StarchGlycollate 2.00 Magnesium stearate 2.00 Total weight 200.00

[0069] The doxazosin mesylate, darifenacin hydrobromide,microcrystalline cellulose, lactose and sodium starch glycollate wereblended together, passed through a screen, then blended again. The blendwas lubricated with magnesium stearate and compressed using a tabletpress. The resulting tablet was then given a film coating.

Example 4

[0070] Combination immediate release doxazosin/controlled releasedarifenacin tablet: Ingredient % w/w Doxazosin Mesylate 4.05Microcrystalline Cellulose 125.28 Lactose 66.67 Sodium Starch Glycollate2.00 Magnesium stearate 4.00 Darifenacin hydrobromide 17.857Methylhydroxypropyl cellulose 114.400 Calcium phosphate dibasic 65.743Total weight 400.000

[0071] The doxazosin mesylate, microcrystalline cellulose, lactose andsodium starch glycollate were blended together, passed through a screen,then blended again. The blend was then lubricated with magnesiumstearate.

[0072] The darifenacin hydrobromide, methylhydroxypropyl cellulose andcalcium phosphate dibasic were blended together, passed through ascreen, then blended again. The blend was then lubricated with magnesiumstearate.

[0073] The individual blends were then compressed on a bi-layer tabletpress. The resulting tablet was then given a film coating.

Example 5

[0074] Controlled release darifenacin tablet: Ingredient % w/wDarifenacin hydrobromide 17.857 Methylhydroxypropyl cellulose 114.400Calcium phosphate dibasic 65.743 Magnesium stearate 2.000 Total weight200.000

[0075] The darifenacin hydrobromide, methylhydroxypropyl cellulose andcalcium phosphate dibasic were blended together, passed through ascreen, then blended again. The blend was lubricated with magnesiumstearate and compressed using a tablet press. The resulting tablet wasthen given a film coating.

[0076] The individual components of a combination of analpha-adrenoceptor antagonist and a muscarinic antagonist can be testedin vivo in an anaesthetized beagle dog model (see, Kenny, et al., Urol.44, 52-57 (1994) in which urethral pressure and/or bladder function aremeasured. However, the unexpected advantage of the combination can onlybe determined, and thus becomes apparent, on evaluation of symptoms, anassessment that can only be carried out in man.

[0077] The combination of an alpha-adrenoceptor antagonist and amuscarinic antagonist can be tested clinically, typically orally, inhumans. Each component is administered singly at different times to apopulation of male patients, each component being administered inconjunction with the International Prostate Symptom Score (IPSS)questionnaire (see, Barry, et al., J. Urol., 148, 1549-1563 (1992))which evaluated patient satisfaction. By administering each componentsingly, it is meant that one component is administered, followed at alater time by the second component after having allowed an appropriatetime for washout of the first component. After the washout period foreach component administered singly, the components are co-administeredin a manner such that both components co-operate pharmacokinetically,preferably such that fully effective drug plasma levels of both agentswill be obtained. Co-administration is evaluated according to IPSSquestionnaires mentioned above, thereby providing a basis for comparisonof the effects of co-administration with that for each singleadministration. The efficacy of the present invention is demonstrated bythe results of the IPSS questionnaire.

I claim:
 1. A product comprising a first pharmaceutically acceptablecomposition comprising an alpha-adrenoceptor antagonist and a secondpharmaceutically acceptable composition comprising a muscarinicantagonist, wherein said product is a combined preparation forsimultaneous, separate or sequential use of said first composition andsaid second composition.
 2. The product of claim 1 wherein saidalpha-adrenoceptor antagonist in said first composition isnon-selective.
 3. The product of claim 1 wherein said alpha-adrenoceptorantagonist in said first composition is selective for α₁ receptors. 4.The product of claim 3 wherein said alpha-adrenoceptor antagonist insaid first composition is selected from the group consisting of4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline,doxazosin, tetrazosin, abanoquil, prazosin, and indoramin orpharmaceutically acceptable salts thereof.
 5. The product of claim 1wherein said muscarinic antagonist in said second composition isnon-selective.
 6. The product of claim 1 wherein said muscarinicantagonist in said second composition is selective for M₃ receptors. 7.The product of claim 1 wherein said muscarinic antagonist in said secondcomposition is selected from the group consisting of darifenacin,tolterodine and oxybutynin or pharmaceutically acceptable salts thereof.8. The product of claim 1 wherein said muscarinic antagonist isdarifenacin or a pharmaceutically acceptable salt thereof.
 9. Theproduct of claim 1 wherein said first composition comprises doxazosinand said second composition comprises darifenacin or a pharmaceuticallyacceptable salt of either thereof.
 10. The product of claim 1 whereinsaid first composition comprises4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolineand said second composition comprises darifenacin or a pharmaceuticallyacceptable salt of either thereof.
 11. A medicament comprising analpha-adrenoceptor antagonist in combination with a muscarinicantagonist.
 12. The medicament of claim 11 wherein saidalpha-adrenoceptor antagonist is non-selective.
 13. The medicament ofclaim 11 wherein said alpha-adrenoceptor antagonist is selective for α₁receptors.
 14. The medicament of claim 11 wherein saidalpha-adrenoceptor antagonist is selected from the group consisting of4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline,doxazosin, tetrazosin, abanoquil, prazosin, and indoramin orpharmaceutically acceptable salts thereof.
 15. The medicament of claim11 wherein said muscarinic antagonist is non-selective.
 16. Themedicament of claim 11 wherein said muscarinic antagonist is selectivefor M₃ receptors.
 17. The medicament of claim 11 wherein said muscarinicantagonist is selected from the group consisting of darifenacin,tolterodine and oxybutynin or pharmaceutically acceptable salts thereof.18. The medicament of claim 11 wherein said muscarinic antagonist isdarifenacin, or a pharmaceutically acceptable salt thereof.
 19. Themedicament of claim 11 wherein said alpha-adrenoceptor antagonist isdoxazosin and said muscarinic antagonist is darifenacin, orpharmaceutically acceptable salts of either thereof.
 20. The medicamentof claim 11 wherein said alpha-adrenoceptor antagonist is4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolineand said muscarinic antagonist is darifenacin, or pharmaceuticallyacceptable salts of either thereof.
 21. A pharmaceutical compositioncomprising an alpha-adrenoceptor antagonist, a muscarinic antagonist anda pharmaceutically acceptable carrier.
 22. The composition of claim 21wherein said alpha-adrenoceptor antagonist is non-selective or selectivefor α₁ receptors.
 23. The composition of claim 21 wherein saidalpha-adrenoceptor antagonist is selected from the group consisting of4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline,doxazosin, tetrazosin, abanoquil, prazosin, and indoramin orpharmaceutically acceptable salts thereof.
 24. The composition of claim21 wherein said muscarinic antagonist is non-selective or selective forM₃ receptors.
 25. The composition of claim 21 wherein said muscarinicantagonist is selected from the group consisting of darifenacin,tolterodine and oxybutynin or pharmaceutically acceptable salts thereof.26. The composition of claim 21 wherein said muscarinic antagonist isdarifenacin, or a pharmaceutically acceptable salt thereof.
 27. Thecomposition of claim 21 wherein said alpha-adrenoceptor antagonist isdoxazosin and said muscarinic antagonist is darifenacin, orpharmaceutically acceptable salts of either thereof.
 28. The compositionof claim 21 wherein said alpha-adrenoceptor antagonist is4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolineand said muscarinic antagonist is darifenacin, or pharmaceuticallyacceptable salts of either thereof.
 29. A method for treating the lowerurinary tract symptoms associated with benign hyperplasia in mammalscomprising administering to a mammal in need thereof an effective amountof an alpha-adrenoceptor antagonist in combination with a muscarinicantagonist.
 30. The method of claim 29 wherein said alpha-adrenoceptorantagonist and said muscarinic antagonist is administeredsimultaneously.
 31. The method of claim 29 wherein saidalpha-adrenoceptor antagonist and said muscarinic antagonist isadministered separately.
 32. The method of claim 29 wherein saidalpha-adrenoceptor antagonist and said muscarinic antagonist isadministered sequentially.
 33. The method of claim 29 wherein thealpha-adrenoceptor antagonist is non-selective or selective for α₁receptors.
 34. The method of claim 29 wherein said alpha-adrenoceptorantagonist is selected from the group consisting of4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline,doxazosin, tetrazosin, abanoquil, prazosin, and indoramin orpharmaceutically acceptable salts thereof.
 35. The method of claim 29wherein said muscarinic antagonist is non-selective or selective for M₃receptors.
 36. The method of claim 29 wherein said muscarinic antagonistis selected from the group consisting of darifenacin, tolterodine andoxybutynin or pharmaceutically acceptable salts thereof.
 37. The methodof claim 29 wherein said muscarinic antagonist is darifenacin, or apharmaceutically acceptable salt thereof.
 38. The method of claim 29wherein said alpha-adrenoceptor antagonist is doxazosin and saidmuscarinic antagonist is darifenacin, or pharmaceutically acceptablesalts of either thereof.
 39. The method of claim 29 wherein saidalpha-adrenoceptor antagonist is4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolineand said muscarinic antagonist is darifenacin, or pharmaceuticallyacceptable salts of either thereof.